Axle component separated ion-pair recognition by a neutral heteroditopic [2]rotaxane

Article abstract of DOI:10.1039/c3cc48905a

A neutral heteroditopic pyridine N-oxide axle containing [2]rotaxane, synthesised via sodium cation templation, displays cooperative recognition of alkali metal cation-halide anion ion-pairs in an unprecedented axle component separated ion-pair binding fa

Full text of DOI:10.1039/c3cc48905a

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Axle component separated ion-pair recognition by
a neutral heteroditopic [2]rotaxane†
Cite this: Chem. Commun., 2014,
50, 1540
Richard C. Knighton and Paul D. Beer*
Received 21st November 2013,
Accepted 16th December 2013
DOI: 10.1039/c3cc48905a
www.rsc.org/chemcomm
A neutral heteroditopic pyridine N-oxide axle containing [2]rotax- containing a pyridine N-oxide axle component. The target
ane, synthesised via sodium cation templation, displays cooperative heteroditopic rotaxane contains a heteroditopic macrocycle which
recognition of alkali metal cation-halide anion ion-pairs in an consists of a calix[4]diquinone cation recognition site covalently
unprecedented axle component separated ion-pair binding fashion. linked to a 3,5-bis amide functionalised pyridine anion binding
motif, together with a pyridine N-oxide axle component where the
As a consequence of the paramount importance of charged species resulting interlocked host system is designed to recognise
in chemical, biological, environmental and industrial processes, the alkali metal cation-halide anion ion-pairs in an unprecedented
construction of receptors for cation and anion recognition is an area ‘axle-separated’ ion-pair binding fashion (Fig. 1).
of supramolecular chemistry that is forever expanding. There is
The synthesis of the new heteroditopic macrocyclic compo-
compelling evidence that the binding affinities and selectivity trends nent 1 of the rotaxane was achieved via a multi-step pathway11,12
of monotopic receptor systems for charged guests are in some as described in the ESI† (see ESI† for synthesis and X-ray crystal
instances influenced significantly by the nature of counterions. With structure). Preliminary 1H NMR experiments were undertaken to
this in mind attention has turned towards the innovative design confirm pseudorotaxane formation between macrocycle 1 and
of heteroditopic receptors which through favourable cooperative 3,5-bis-hexyl-amide pyridine N-oxide thread derivative 2 in CDCl3
electrostatic interactions, allosteric effects and preorganisation, in the presence of one equivalent of sodium cation (see ESI,†
have been shown to enhance the efficacy of charged guest S4.1). Upon addition of the pyridine N-oxide thread 2 broadening
recognition with promising applications as superior extraction and upfield shifts of macrocycle hydroquinone protons d were
and membrane transport agents.1,2
observed, indicative of interpenetration.
Heteroditopic receptors can be divided into two classes, where the
The synthesis of the target rotaxane was accomplished
cation and anion are bound as a contact or a separated ion-pair. using a threading-followed-by-stoppering strategy utilising the
The additional challenge to the construction of separated ion-pair copper-catalysed azide–alkyne cycloaddition (CuAAC) reaction.
receptors lies in the requirement to overcome the electrostatic
interaction between the constituent cation or anion from its
counterpart.3 Mechanically interlocked molecules can be fabricated
to contain topologically unique three dimensional cavities for mole-
cular recognition and sensing applications.4–6 In this communica-
tion, we report the first example of a neutral heteroditopic interlocked
rotaxane host system which is capable of binding alkali metal halides
as ‘axle-separated’ ion-pairs whereby halide anion binding affinity is
enhanced by the presence of the alkali metal cation.7
We have recently exploited alkali8 and lanthanide metal
cation,9 and chloride anion templation10 to prepare rotaxanes
Chemistry Research Laboratory, Department of Chemistry, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, UK. E-mail: paul.beer@chem.ox.ac.uk
† Electronic supplementary information (ESI) available. CCDC 970552. For ESI
Fig. 1 Cartoon representation of proposed heteroditopic [2]rotaxane
capable of axle-separated ion-pair binding.
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc48905a
1540 | Chem. Commun., 2014, 50, 1540--1542
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Scheme 1 Synthesis of heteroditopic [2]rotaxane
5 by a threading-
followed-by-stoppering strategy.
Scheme 2 Molecular pirouetting of heteroditopic [2]rotaxane upon addi-
tion of sodium cations.
The macrocycle 1 was stirred with equimolar amounts of
axle precursor 39 and sodium perchlorate, together with two
equivalents of alkyne functionalised terphenyl stopper 412 and
diisopropylethylamine (DIPEA) in chloroform solution in the
presence of catalytic amount of Cu(MeCN)4PF6 and TBTA at
room temperature for 36 hours (Scheme 1). After sequestration
of the metal template and purification by size-exclusion and
preparative thin layer chromatography the target [2]rotaxane 5
was isolated in 62% yield and characterised by 1H and 13C NMR
spectroscopy and high resolution mass spectrometry, with the
interlocked nature confirmed using 1H–1H ROESY spectroscopy
(see ESI,† S3.1).
(4: 1) the internal and external bis-amide pyridyl and pyridine N-
oxide protons a, b and a, b of the respective macrocycle and axle
were observed to shift downfield (Fig. 2).
The downfield shifts of a and a are indicative of a polarising
hydrogen bonding interaction of these protons with the chloride
anion. The shift of both these protons suggests the halide anion is
binding within the interlocked amide cavity of the rotaxane formed
between axle and macrocycle components.14 Similar downfield
shifts of a, b and a, b were also observed for the other halides.
The titration data was analysed using the WinEQNMR215 program,
monitoring the internal axle proton a, to determine 1 : 1 stoichio-
metric association constants reported in Table 1.
It is noteworthy that the role of the sodium cation is crucial
in the formation of the interlocked structure; when the synthesis
was repeated in the absence of the metal the yield of rotaxane
was significantly reduced to o10%.13 It was found that upon
removal of the sodium cation metal template from the resultant
[2]rotaxane using EDTA that a molecular motion occurs; in the
presence of the alkali metal the pyridine N-oxide is coordinated
to the metal cation with the axle pyridine N-oxide oxygen
pointing towards the calixdiquinone moiety. Upon removal of
the template however, the pyridine N-oxide motif pirouettes
within the macrocyclic cavity, forming hydrogen bonds with
the 3,5-bis amide functionalised pyridine motif of the macro-
In the absence of a metal cation the observed halide binding
affinities are modest and are all of comparable magnitude. This
1
cycle (Scheme 2) as determined by H–1H ROESY spectroscopy
(see ESI,† S3.2).
Preliminary 1H NMR anion titration experiments were
undertaken to determine the affinity of the rotaxane to halides
in the absence of a metal cation. Upon addition of increasing
amounts of TBACl to a solution of [2]rotaxane 5 in CDCl3/CD3OD
Fig. 2 1H NMR spectra of (a) rotaxane 5 plus 3 equivalents of TBAÁCl;
(b) rotaxane 5 plus 1 equivalent of TBAÁCl; (c) rotaxane 5 (500 MHz, 4 : 1
CDCl3/CD3OD, 298 K).
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Table 1 Anion association constants Ka (MÀ1) for rotaxane 5 in the
absence and presence of one equivalent of metal cation (4 : 1 CDCl3/
CD3OD, 298 K); errors in parentheses; alkali metals cations added as LiPF6,
NaOTf and KPF6
binding complementarity between the heteroditopic rotaxane
and the sodium chloride ion-pair. Chloride binding affinity is
also enhanced by almost an order of magnitude in the presence
of potassium. Large cooperativity factors are also noted for
bromide, of 10.6 and 7.2 for sodium and potassium respectively.
With lithium, a modest increase in the strength of bromide
anion binding was observed although no significant enhance-
ment of the binding affinity of chloride was noted.
In summary a neutral heteroditopic [2]rotaxane has been
synthesised via a sodium cation templated threading-followed-
by-stoppering methodology. The resultant rotaxane host system
has been demonstrated to act as either a monotopic or hetero-
ditopic host for halide anions or alkali metal halide ion-pairs
respectively. It was found that upon the addition of sodium and
potassium alkali metal cations the chloride and bromide anion
binding affinities were significantly amplified due to conforma-
tional reorganisation of the host and favourable electrostatic
contributions, with the greatest complementary found for
sodium chloride, displaying over an order of magnitude
enhancement for the halide in the presence of the metal cation.
This increase in binding affinity occurs from greater preorga-
nisation of the receptor when a cation is bound and operates
through an unprecedented ‘axle-separated’ recognition of the
ion-pair by the heteroditopic rotaxane host.
Cation
Association constant/MÀ1
Cooperativity factora
ClÀ
BrÀ
None
Li+
71 (7)
80 (3)
1079 (33)
676 (85)
88 (8)
166 (6)
930 (134)
633 (91)
92 (12)
—
1.1
15.1
9.5
—
1.9
10.6
7.2
—
Na+
K+
None
Li+
Na+
K+
IÀ
None
a
Cooperativity factor is calculated by Ka (anion, ion pair)/Ka (anion,
free).
may be rationalised by consideration of the rotaxane having to
undergo conformational reorganisation where upon pirouetting
of the axle results in favourable inter-component axle pyridine
N-oxide-macrocycle bis-amide pyridyl hydrogen bonds being
broken in order bind the halide anion.
Analogous halide anion titration experiments were undertaken
in the presence of an alkali metal cation with the expectation that
the bound metal cation would help preorganise the rotaxane
through conformational reorganisation and, in addition through
favourable electrostatic interactions, increase the interlocked
host’s anion binding affinity. Anion titrations were performed
in the presence of one equivalent of an alkali metal cation as
non-coordinating hexafluorophosphate and triflate salts and
WinEQNMR2 analysis of the titration data determined 1 : 1
stoichiometric association constant values shown in Table 1
(see ESI,† S4.3 and Fig. 3 for anion-binding curves and 1H NMR
spectra respectively).
R.C.K. thanks a Helmore Award for a DPhil studentship and
Diamond Light Source for the award of beam time on I19
(MT1858).
Notes and references
1 S. K. Kim and J. L. Sessler, Chem. Soc. Rev., 2010, 39, 3784–3809.
2 A. J. McConnell and P. D. Beer, Angew. Chem., Int. Ed., 2012, 51,
5052–5061.
3 J. M. Mahoney, A. M. Beatty and B. D. Smith, J. Am. Chem. Soc., 2001,
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4 C. G. Collins, E. M. Peck, P. J. Kramer and B. D. Smith, Chem. Sci.,
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5 G. T. Spence and P. D. Beer, Acc. Chem. Res., 2013, 46, 571–586.
6 M. J. Chmielewski, J. J. Davis and P. D. Beer, Org. Biomol. Chem.,
2009, 7, 415–424.
7 Smith et al. have previously reported a salt binding [2]rotaxane
whereby anion binding is not affected by the presence of a cation.
M. J. Deetz, R. Shukla and B. D. Smith, Tetrahedron, 2002, 58,
799–805.
It is noteworthy that a significant increase in the magnitudes
of chloride and bromide anion association constants is observed
in the presence of sodium and potassium.16 In the case of
chloride the cooperativity factor in the presence of sodium
cations is over 15-fold, suggesting a high degree of host–guest
8 L. M. Hancock and P. D. Beer, Chem. Commun., 2011, 47, 6012–6014.
9 F. Zapata, O. A. Blackburn, M. J. Langton, S. Faulkner and P. D. Beer,
Chem. Commun., 2013, 49, 8157–8159.
10 J. M. Mercurio, F. Tyrrell, J. Cookson and P. D. Beer, Chem.
Commun., 2013, 49, 10793–10795.
11 M. D. Lankshear, N. H. Evans, S. R. Bayly and P. D. Beer, Chem.–Eur.
J., 2007, 13, 3861–3870.
12 A. V. Leontiev, C. A. Jemmett and P. D. Beer, Chem.–Eur. J., 2011, 17,
816–825.
13 As determined by NMR spectroscopy of the crude reaction mixture.
14 Indeed the smaller shift of macrocycle proton a is a result of the fact
that in the free rotaxane this proton is already hydrogen bonding to
the N-oxide oxygen, supporting the postulated molecular motion.
15 M. J. Hynes, J. Chem. Soc., Dalton Trans., 1993, 311–312.
16 Titrations performed with iodide in the presence of alkali metal
cations in all cases resulted in competitive ion-pair sequestration
with possible precipitation.
Fig. 3 1H NMR spectra of (a) rotaxane 5ÁNaOTf plus 3 equivalents of TBAÁ
Cl; (b) rotaxane 5ÁNaOTf plus 1 equivalent of TBAÁCl; (c) rotaxane 5ÁNaOTf
(500 MHz, 4 : 1 CDCl3/CD3OD, 298 K).
1542 | Chem. Commun., 2014, 50, 1540--1542
This journal is ©The Royal Society of Chemistry 2014